The mechanisms of liver injury from cold storage and reperfusion are not completely understood. The aim of the present study was to investigate whether the inactivation of Kupffer cells (KCs) by gadolinium chloride (GdCl3) modulates ischemia-reperfusion injury in the rat liver. Hepatic function was assessed using an isolated perfused rat liver model. In livers subjected to cold storage at 4 degees C in University of Wisconsin solution for 24 hrs and to 20 min rewarm-ing ischemia, oxygen uptake was markedly decreased, Kupffer cell phagocytosis was stimulated, releases of purine nucleoside phosphorylase and lactate dehydrogenase were increased as compared with control livers. Pretreatment of rats with GdCl3, a selective KC toxicant, suppressed Kupffer cell activity, and reduced the grade of hepatic injury induced by ischemia-reperfusion. While the initial mixed function oxidation of 7-ethoxycoumarin was not different from that found in the control livers, the subsequent conjugation of its meta-bolite to sulfate and glucuronide esters was suppressed by ischemia-reperfusion. GdCl3 restored sulfation and glucuronidation capacities to the level of the control liver. Our findings suggest that Kupffer cells could play an important role in cold/warm ischemia-reperfusion hepatic injury.